Genetic regulation of linear growth

Linear growth occurs at the growth plate. Therefore, genetic defects that interfere with the normal function of the growth plate can cause linear growth disorders. Many genetic causes of growth disorders have already been identified in humans. However, recent genome-wide approaches have broadened our knowledge of the mechanisms of linear growth, not only providing novel monogenic causes of growth disorders but also revealing single nucleotide polymorphisms in genes that affect height in the general population. The genes identified as causative of linear growth disorders are heterogeneous, playing a role in various growth-regulating mechanisms including those involving the extracellular matrix, intracellular signaling, paracrine signaling, endocrine signaling, and epigenetic regulation. Understanding the underlying genetic defects in linear growth is important for clinicians and researchers in order to provide proper diagnoses, management, and genetic counseling, as well as to develop better treatment approaches for children with growth disorders

Characteristics of Snow Depth and Snow Phenology in the High Latitudes and High Altitudes of the Northern Hemisphere from 1988 to 2018

Snow cover is an important part of the Earth’s surface and its changes affect local and even global climates due to the high albedo and heat insulation. However, it is difficult to directly compare the results of previous studies on changes in snow cover in the Northern Hemisphere mainland (NH) due to the use of different datasets, research methods, or study periods, and a lack comparison in terms of the differences and similarities at high latitudes and high altitudes. By using snow depth datasets, we analyzed the spatio-temporal distributions and variations in snow depth (SD) and snow phenology (SP) in the NH and nine typical areas. This study revealed that SD in the NH generally decreased significantly (p < 0.01) from 1988 to 2018, with a rate of −0.55 cm/decade. Changes in SD were insignificant at high altitudes, but significant decreases were found at high latitudes. With regard to SP, the snow cover onset day (SCOD) advanced in 31.57% of the NH and was delayed in 21.10% of the NH. In typical areas such as the Rocky Mountains, the West Siberian Plain, and the Central Siberian Plateau, the SCOD presented significant advancing trends, while a significant delay was the trend observed in the Eastern European Plain. The snow cover end day (SCED) advanced in 37.29% of the NH and was delayed in 14.77% of the NH. Negative SCED trends were found in most typical areas. The snow cover duration (SCD) and snow season length (SSL) showed significant positive trends in the Rocky Mountains, while significant negative trends were found in the Qinghai–Tibet Plateau. The results of this comprehensive comparison showed that most typical areas were characterized by decreased SD, advanced SCOD and SCED, and insignificantly increasing SCD and SSL trends. The SCD and SSL values were similar at high latitudes, while the SSL value was larger than the SCD value at high altitudes. The SD exhibited similar interannual fluctuation characteristics as the SCD and SSL in each typical area. The SCD and SSL increased (decreased) with advanced (delayed) SCODs

Characteristics of Snow Depth and Snow Phenology in the High Latitudes and High Altitudes of the Northern Hemisphere from 1988 to 2018

Snow cover is an important part of the Earth’s surface and its changes affect local and even global climates due to the high albedo and heat insulation. However, it is difficult to directly compare the results of previous studies on changes in snow cover in the Northern Hemisphere mainland (NH) due to the use of different datasets, research methods, or study periods, and a lack comparison in terms of the differences and similarities at high latitudes and high altitudes. By using snow depth datasets, we analyzed the spatio-temporal distributions and variations in snow depth (SD) and snow phenology (SP) in the NH and nine typical areas. This study revealed that SD in the NH generally decreased significantly (p < 0.01) from 1988 to 2018, with a rate of −0.55 cm/decade. Changes in SD were insignificant at high altitudes, but significant decreases were found at high latitudes. With regard to SP, the snow cover onset day (SCOD) advanced in 31.57% of the NH and was delayed in 21.10% of the NH. In typical areas such as the Rocky Mountains, the West Siberian Plain, and the Central Siberian Plateau, the SCOD presented significant advancing trends, while a significant delay was the trend observed in the Eastern European Plain. The snow cover end day (SCED) advanced in 37.29% of the NH and was delayed in 14.77% of the NH. Negative SCED trends were found in most typical areas. The snow cover duration (SCD) and snow season length (SSL) showed significant positive trends in the Rocky Mountains, while significant negative trends were found in the Qinghai–Tibet Plateau. The results of this comprehensive comparison showed that most typical areas were characterized by decreased SD, advanced SCOD and SCED, and insignificantly increasing SCD and SSL trends. The SCD and SSL values were similar at high latitudes, while the SSL value was larger than the SCD value at high altitudes. The SD exhibited similar interannual fluctuation characteristics as the SCD and SSL in each typical area. The SCD and SSL increased (decreased) with advanced (delayed) SCODs

Spatial regulation of bone morphogenetic proteins (BMPs) in postnatal articular and growth plate cartilage

<div><p>Articular and growth plate cartilage both arise from condensations of mesenchymal cells, but ultimately develop important histological and functional differences. Each is composed of three layers—the superficial, mid and deep zones of articular cartilage and the resting, proliferative and hypertrophic zones of growth plate cartilage. The bone morphogenetic protein (BMP) system plays an important role in cartilage development. A gradient in expression of BMP-related genes has been observed across growth plate cartilage, likely playing a role in zonal differentiation. To investigate the presence of a similar expression gradient in articular cartilage, we used laser capture microdissection (LCM) to separate murine growth plate and articular cartilage from the proximal tibia into their six constituent zones, and used a solution hybridization assay with color-coded probes (nCounter) to quantify mRNAs for 30 different BMP-related genes in each zone. In situ hybridization and immunohistochemistry were then used to confirm spatial expression patterns. Expression gradients for Bmp2 and 6 were observed across growth plate cartilage with highest expression in hypertrophic zone. However, intracellular BMP signaling, assessed by phospho-Smad1/5/8 immunohistochemical staining, appeared to be higher in the proliferative zone and prehypertrophic area than in hypertrophic zone, possibly due to high expression of Smad7, an inhibitory Smad, in the hypertrophic zone. We also found BMP expression gradients across the articular cartilage with BMP agonists primarily expressed in the superficial zone and BMP functional antagonists primarily expressed in the deep zone. Phospho-Smad1/5/8 immunohistochemical staining showed a similar gradient. In combination with previous evidence that BMPs regulate chondrocyte proliferation and differentiation, the current findings suggest that BMP signaling gradients exist across both growth plate and articular cartilage and that these gradients may contribute to the spatial differentiation of chondrocytes in the postnatal endochondral skeleton.</p></div

Expression of genes involved in BMP signaling in articular cartilage.

<p>Relative gene expression (mean ± SEM) of a subset of BMP agonists (top row), BMP functional antagonists (second row), BMP receptors (third row) and downstream signaling modulators (bottom row) in superficial zone (S), middle zone (M) and deep zone (D) of 1-wk old mouse tibial growth plate, measured by a multiplex solution hybridization assay (nCounter). A full list of BMP-related gene and expression values were shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0176752#pone.0176752.s001" target="_blank">S1 Table</a>.</p

In situ hybridization for BMP-related genes in articular and growth plate cartilage.

<p>Formalin fixed, decalcified sections of 1-wk old mouse tibial cartilage were hybridized to DIG-labeled riboprobes, producing a purple color and were visualized by scanning the slides with a ScanScope CS digital scanner using bright field microscopy. Left panel, Mason-trichrome stained sections; middle panel, in situ hybridization without counterstaining; right panel, higher magnification views taken from within the rectangular area indicated in the corresponding middle panel. SZ, superficial zone; MZ, middle zone; DZ, deep zone; RZ, resting zone; PZ, proliferative zone; HZ, hypertrophic zone.</p

Immunohistochemistry for SMADs in articular and growth plate cartilage.

<p>Formalin fixed, decalcified sections of 1-wk old mouse tibial cartilage were stained with anti-pSmad1/5/8 and anti-Smad7 antibody. Signals were developed with DAB substrate (brown color) with no counterstaining. pSmad1/5/8 represents activation of BMP intracellular signaling, while Smad7 is an I-SMAD that functions as a functional antagonist of BMP signaling. SZ, superficial zone; MZ, middle zone; DZ, deep zone; RZ, resting zone; PZ, proliferative zone; HZ, hypertrophic zone.</p

Expression of genes involved in BMP signaling in growth plate cartilage.

<p>Relative gene expression (mean ± SEM) of a subset of BMP agonists (top row), BMP functional antagonists (second row), BMP receptors (third row) and downstream signaling modulators (bottom row) in resting zone (R), proliferative zone (P) and hypertrophic zone (H) of 1-wk old mouse tibial growth plate, measured by a multiplex solution hybridization assay (nCounter). A full list of BMP-related gene and expression values were shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0176752#pone.0176752.s001" target="_blank">S1 Table</a>.</p

Immunohistochemistry for BMP-related proteins in articular and growth plate cartilage.

<p>Formalin fixed, decalcified sections of 1-wk old mouse tibial cartilage were stained with anti-Bmp2, anti-Bmp6, and anti-Grem1 antibody and signals were developed with DAB substrate (brown color). Tissues were counterstained in methyl green and visualized by scanning with a ScanScope CS digital scanner using bright field microscopy. SZ, superficial zone; MZ, middle zone; DZ, deep zone; RZ, resting zone; PZ, proliferative zone; HZ, hypertrophic zone.</p

Laser capture microdissection of mouse articular and growth plate cartilage.

<p><b>(A</b>) Haemotoxylin & eosin stained section of formalin fixed, decalcified 1-wk old mouse proximal tibial cartilage showing the location of zones in the cartilage that were targeted by laser capture microdissection (LCM). <b>(B)</b> Haemotoxylin & eosin stained frozen sections of 1-wk old mouse proximal tibial cartilage after LCM showing regions that were excised for RNA isolation. <b>(C)</b> Relative gene expression (mean ± SEM) of zonal markers used for dissection validation. S, superficial zone; M, middle zone; D, deep zone; R, resting zone; P, proliferative zone; H, hypertrophic zone. Scale bar applies to both (A) and (B).</p